The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one. An important facet of the system is the T cell response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens ("HLA"), or major histocompatibility complexes ("MHCs"), and peptides. The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. See in this regard Male et al., Advanced Immunology (J. P. Lipincott Company, 1987), especially chapters 6-10. The interaction of T cell and complexes of HLA/peptide is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. This mechanism is involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Recently, much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides. See, in this regard, Barinaga, Science 257: 880 (1992); Fremont et al., Science 257: 919 (1992); Matsumura et al., Science 257: 927 (1992); Latron et al., Science 257: 964 (1992).
The mechanism by which T cells recognize cellular abnormalities has also been implicated in cancer. For example, in PCT application PCT/US92/04354, filed May 22, 1992, published on Nov. 26, 1992, and incorporated by reference, a family of genes is disclosed, which are processed into peptides which, in turn, are expressed on cell surfaces, which can lead to lysis of the tumor cells by specific CTLs. The genes are said to code for "tumor rejection antigen precursors" or "TRAP" molecules, and the peptides derived therefrom are referred to as "tumor rejection antigens" or "TRAs". See Traversari et al., Immunogenetics 35: 145 (1992); van der Bruggen et al., Science 254: 1643 (1991), for further information on this family of genes. Also see U.S. Pat. No. 5,342,774, incorporated by reference.
In U.S. Pat. No. 5,405,940, the disclosure of which is incorporated by reference, nonapeptides are taught which bind to the HLA-A1 molecule. The reference teaches that given the known specificity of particular peptides for particular HLA molecules, one should expect a particular peptide to bind one HLA molecule, but not others. This is important, because different individuals possess different HLA phenotypes. As a result, while identification of a particular peptide as being a partner for a specific HLA molecule has diagnostic and therapeutic ramifications, these are only relevant for individuals with that particular HLA phenotype. There is a need for further work in the area, because cellular abnormalities are not restricted to one particular HLA phenotype, and targeted therapy requires some knowledge of the phenotype of the abnormal cells at issue.
The enzyme tyrosinase catalyzes the reaction converting tyrosine to dehydroxyphenylalanine or "DOPA" and appears to be expressed selectively in melanocytes (Muller et al., EMBO J 7: 2715 (1988)). An early report of cDNA for the human enzyme is found in Kwon, U.S. Pat. No. 4,898,814. A later report by Bouchard et al., J. Exp. Med. 169: 2029 (1989) presents a slightly different sequence. A great deal of effort has gone into identifying inhibitors for this enzyme, as it has been implicated in pigmentation diseases. Some examples of this literature include Jinbow, W09116302; Mishima et al., U.S. Pat. No. 5,077,059, and Nazzaropor, U.S. Pat. No. 4,818,768. The artisan will be familiar with other references which teach similar materials.
U.S. patent application Ser. No. 08/081,673, filed Jun. 23, 1993 now U.S. Pat. No. 5,487,974 and incorporated by reference, teaches that tyrosinase may be treated in a manner similar to a foreign antigen or a TRAP molecule--i.e., it was found that in certain cellular abnormalities, such as melanoma, tyrosinase is processed and a peptide derived therefrom forms a complex with HLA molecules on certain abnormal cells. These complexes were found to be recognized by cytolytic T cells ("CTLs"), which then lyse the presenting cells. The ramifications of this surprising and unexpected phenomenon were discussed. Additional peptides have now been found which also act as tumor rejection antigens presented by HLA-A2 molecules. These are described in Ser. No. 08/203,054, filed Feb. 28, 1994 now U.S. Pat. No. 5,530,096 and incorporated by reference.
U.S. patent application Ser. No. 08/233,305 filed Apr. 26, 1994 now U.S. Pat. No. 5,519,117 and incorporated by reference, discloses that, tyrosinase is also processed to an antigen presented by HLA-B44 molecules. The finding was of importance, because not all individuals are HLA-A2.sup.+. The fact that tyrosinase is processed to an HLA-B44 presented peptide, however, does not provide for a universal approach to diagnosis and treatment of all HLA-B44.sup.+ tumors, because tyrosinase expression is not universal. Further, the fact that tyrosinase is expressed by normal cells as well as tumor cells may suggest some caution in the therapeutic area.
Population analysis indicates that about 22-24% of the caucasian population expresses the HLA-B44 molecule. See, e.g., Imanishi, et al., in Tsuji et al., ed., "HLA 1991, Vol. I, XI.sup.th International Histocompatibility Workshop And Conference", Oxford University Press, 1991; Lee in Lee, ed., The HLA System: A New Approach. Springer, pp. 141-178 (1990). Prior work has shown that about 76% of all metastatic melanoma tumors express MAGE-3 (Brasseur, et al., Int. J. Cancer 63: 375-380 (1995)). Thus, approximately 17% of metastatic melanomas in the caucasian population should present complexes of HLA-B44 and MAGE-3 derived peptides on their surfaces, with clear implications for diagnosis and therapy. Five different HLA-B44 alleles have been identified, as can be seen via Fleischhauer, et al., Tissue Antigens 37: 133-137 (1991); Petersdorf, et al., Tissue Antigens 44: 211-216 (1994); Yao, et al., Immunogenetics 40: 310; Yao, et al., Human Immunol 42: 54-60 (1995); Yao, et al., Immunogenetics 41: 387 (1995). Among the caucasian population which expresses HLA-B44, 61% present the HLA-B*4402 allele, and 36% present allele HLA-B*4403. See Yao, et al., Human Immunol. 42: 54-60 (1995). There is a single difference between these two alleles which occurs at amino acid 156. In HLA-B*4402, this position is occupied by Asp, while it is occupied by Leu in HLA-B*4403. Bone marrow allograft rejections, and Graft versus Host disease have been observed between donors and recipients which differ with respect to the HLA-B*4402 and HLA-B*4403 alleles. Since amino acid 156 is located in the middle of an .alpha.2 helix and extends into the peptide binding site, it was of interest to determine if these different HLA-B44 alleles present different peptides.
Khanna, et al., J. Exp. Med. 176: 169-179 (July 1992), disclose an HLA-B44 binding peptide, which is discussed further infra. The Khanna peptide is not related to the peptides claimed herein.
Kita, et al., Hepatology 18 (5): 1039-1044 (1993), teach a 20 amino acid peptide alleged to bind to HLA-B44 and to provoke lysis.
Thorpe, et al., Immunogenetics 40: 303-305 (1994), discuss alignment of two peptides found to bind to HLA-B44, and suggest a binding motif generally. The Thorpe disclosure speaks of a negatively charged amino acid at position 2, and one at position 9 which may be hydrophobic, or positively charged.
Fleischhauer, et al., Tissue Antigens 44: 311-317 (1994) contains a survey of HLA-B44 binding peptides.
It has now been found that the MAGE-3 tumor rejection antigen precursor is processed to a tumor rejection antigens presented by HLA-B44 molecules. It is of interest that this peptide differs from a peptide also derived from MAGE-3 and known to bind to HLA-A1, by a single, added amino acid at the N-terminus. This, inter alia, is the subject of the invention disclosure which follows.